Biogerontology (2018) 19:497–517

https://doi.org/10.1007/s10522-018-9772-6 (0123456789().,-volV)(0123456789().,-volV)

REVIEW ARTICLE

Adult stem cell maintenance and tissue regeneration around the clock: do impaired stem cell clocks drive age-associated tissue degeneration?

Eve H. Rogers . John A. Hunt . Vanja Pekovic-Vaughan

Received: 31 March 2018 / Accepted: 19 September 2018 / Published online: 29 October 2018 Ó The Author(s) 2018

Abstract Human adult stem cell research is a highly environment. Circadian rhythms deteriorate with age prolific area in modern tissue engineering as these at both the behavioural and molecular levels, leading cells have significant potential to provide future to age-associated changes in downstream rhythmic cellular therapies for the world’s increasingly aged tissue physiology in humans and rodent models. In this population. Cellular therapies require a smart bioma- review, we highlight recent advances in our knowl- terial to deliver and localise the cell population; edge of the role of circadian clocks in adult stem cell protecting and guiding the stem cells toward prede- maintenance, driven by both cell-autonomous and termined lineage-specific pathways. The cells, in turn, tissue-specific factors, and the mechanisms by which can provide protection to biomaterials and increase its they co-opt various cellular signaling pathways to longevity. The right combination of stem cells and impose temporal control on stem cell function. Future biomaterials can significantly increase the therapeutic research investigating pharmacological and lifestyle efficacy. Adult stem cells are utilised to target many interventions by which circadian rhythms within adult changes that negatively impact tissue functions with stem niches can be manipulated will provide avenues age. Understanding the underlying mechanisms that for temporally guided cellular therapies and smart lead to changes brought about by the ageing process is biomaterials to ameliorate age-related tissue deterio- imperative as ageing leads to many detrimental effects ration and reduce the burden of chronic disease. on stem cell activation, maintenance and differentia- tion. The circadian clock is an evolutionarily con- Keywords Adult stem cells Á Circadian rhythms Á served timing mechanism that coordinates physiology, Aging Á Proliferation Á Differentiation Á Mechanical metabolism and behavior with the 24 h solar day to stimulation provide temporal tissue homeostasis with the external

E. H. Rogers Á V. Pekovic-Vaughan (&) An introduction to adult stem cells Institute of Ageing and Chronic Disease, University of Liverpool, The William Henry Duncan Building, 6 West Derby Street, Liverpool L7 8TX, UK Pioneering experiments in stem cell research are often e-mail: [email protected] credited to Canadian scientists Till and McCulloch in 1961–1963, who were the first to carry out clonal J. A. Hunt colony formation assays on hematopoietic stem cells School of Science and Technology, Nottingham Trent University, Clifton Campus, College Drive, (HSCs) in murine bone marrow, indicating their Nottingham NG11 8NS, UK 123 498 Biogerontology (2018) 19:497–517 multipotency (Becker et al. 1963). Since then, stem vessels and bone marrow (mesenchymal and cell research has progressed exponentially, with hematopoietic stem cells), the brain (neural stem numerous scientific breakthroughs. In this review, cells), skin (epidermal stem cells), skeletal muscle we will introduce some of the well-studied as well as (muscle satellite cells/myogenic stem cells), teeth emerging mechanisms regulating adult stem cell (dental pulp stem cells), heart (cardiac stem cells), gut function and how these become affected during (intestinal stem cells), liver (hepatic stem cells), ageing. Recently, there has been an increased interest ovarian epithelium (ovarian stem cells), breast (mam- in several research areas pertaining to stem cell mary stem cells) and testis (testicular stem cells). function in 3D environments including the role ASCs are multipotent and are, by that definition, circadian clocks play in stem cell physiology (tempo- limited to giving rise to different cell types from ral regulation) as well as the role of mechano- their tissue of origin. They divide either symmetri- transduction processes in modulating stem cell func- cally to produce two identical cells which self- tion (spatial regulation). This review aims to bring renew, proliferate and expand in number, or asym- together developments in these exciting research fields metrically to produce one identical stem cell and and reveal important areas for novel research to be one committed daughter cell which maintain pro- conducted. Further insights into these spatio-temporal geny population (Fig. 1). The form of division that mechanisms will allow better understanding of envi- occurs depends on developmental and environmental ronmental cues that regulate stem cell physiology signals. It has been suggested that most ASCs have in vivo and aid future design of new stem cell therapies the ability to switch between asymmetric and for age-related diseases. symmetric division models, and that the balance Stem cells are characterized by their extraordinary between the two is often altered in disease states capacity to both self-renew through cell divisions and (Morrison and Kimble 2006). to differentiate into a wide range of tissue-specific When comparing embryonic stem cells to ASCs, cells in response to endogenous or external stimuli. It embryonic stem cells (ESCs) are pluripotent, meaning is these regenerative roles that stem cells within each that they are capable of differentiating into any one of tissue niche carry out to repair tissues following the three germ layers; endoderm, mesoderm or injury/disease and maintain tissues throughout life- ectoderm. Since their discovery, there has been a course. Indeed, adult stem cells (ASCs), which can be great interest in their use in regenerative medicine and more appropriately referred to as adult progenitor tissue engineering, due to their pluripotent differenti- cells, are being used to treat an ever-increasing array ation capabilities. However, the pluripotency of ESCs of human conditions, varying from heart disease to makes it difficult to direct their differentiation in a leukaemia. But in order for ASCs to become a reliable, long term and reproducible manner. Further- therapeutic reality, these tissue regenerative processes more, many in vivo studies have shown embryonic must fully be understood, and the environmental stem cells, following implantation, can spontaneously factors that regulate this regeneration process fully differentiate and form a type of tumour called a uncovered, which is vital for the repair and replenish- teratoma (Thomson et al. 1998). ASCs do not ment of most tissues in the body. demonstrate these limitations in in vivo models, and Adult stem cell (ASC) classification has become so there is a substantial interest in using ASCs in highly complex since the original terms ‘haematopoi- regenerative medicine. However, ASCs are more etic’ and ‘mesenchymal’ covered the main types of committed than ESCs, and so they have a more these pluripotent cells. Currently, they tend to be limited differentiation potential. Nevertheless, ASCs classified based on their tissue of origin and differen- such as bone marrow derived mesenchymal stem cells tiation potential, and one should perhaps increasingly (BM-MSCs), hematopoietic stem cells (HSCs) from replace the use of the term adult ‘stem cells’ in favour bone marrow and cord blood, and adipose-derived of adult ‘progenitor cells’. Adult progenitor cells, stem cells (ADSCs) are all attractive targets as they being somatic stem cells, can be derived from all parts still have varied differentiation potentials and are able of the body, where they are found in tissue-specific to differentiate into a variety of cell types. For stem cell niches. Progenitor cells have been derived example, BM-MSCs are able to differentiate into and utilised from cord and peripheral blood, blood bone, cartilage, fat, tendon, muscle, and marrow 123 Biogerontology (2018) 19:497–517 499

Fig. 1 Stem Cell Division. a Adult stem cells are capable of produce one identical stem cell and one committed daughter dividing either symmetrically, to produce two identical stem cell. b The hierarchy of stem cell division cells or two identical daughter cells, or asymmetrically, to stroma (Pittenger et al. 1999), and HSCs are able to deviation from the 24 h cycle provides a mechanism differentiate into both myeloid (including monocytes, for alignment for the internal time-keeping system, macrophages, neutrophils, basophils, eosinophils, ery- allowing the rhythm to be ‘‘reset’’ where necessary throcytes, dendritic cells, and megakaryocytes or (Pittendrigh 1960). In line with this anticipatory daily platelets) and lymphoid (T cells, B cells, and natural role of the circadian clocks, there are a number of killer cells) lineages of blood cells. These ASCs are mammals living in extreme conditions without a also advantageous as they present an ease of harvest, functioning circadian clock, which can be restored isolation and expansion in vitro, when compared to upon appropriate environmental stimuli. For example, embryonic stem cells. The impressive multi-lineage indigenous Arctic reindeer do not express circadian differentiation potential of ASCs is made possible by rhythms during the periods of constant sunlight in the the broad combination of chemical, biological and summer or constant darkness in winter months in the physical signals present in their stem cell niches, Arctic (Lu et al. 2010). Similarly, free-living Arctic which direct and control their fate. ground squirrels do not express circadian rhythms during hibernation in the winter but do exhibit robust daily circadian body temperature oscillations over A brief introduction to the body’s pacemaker: 24 h during their active season (Williams et al. the circadian clock 2011, 2017). In this way, such mammals are able to restablish circadian rhythmicity coincident with emer- An important evolutionarily conserved mechanism gence to the surface and the resumption of surface that becomes altered with age is the circadian clock, activity (Williams et al. 2012). the body’s innate time-keeping system. Circadian The mammalian circadian rhythms are orchestrated rhythms are a subset of biological rhythms, which by a hierarchy of oscillators. The master clock located have a period of approximately 24 h. The foundation within the suprachiasmatic nucleus (SCN) in the of circadian rhythmicity research is often dated back to anterior hypothalamus of the brain, coordinates a the work done by Colin Pittendrigh and Jurgen number of independent central nervous system (CNS) Aschoff. These pioneers have defined the basis of and peripheral tissue oscillators, acting as a pacemaker circadian entrainment. Pittendrigh (1960) showed that to regulate a coherent rhythm at the level of the whole

123 500 Biogerontology (2018) 19:497–517 organism (Yamazaki et al. 2000). The input pathway There has been a number of recent exciting studies for the master pacemaker encompasses the light documenting how ageing affects the molecular clock information that enters the retina through retinal in several tissues (Kondratov et al. 2006). Mouse photoreceptors, which is relayed to and entrains the models of genetic clock disruption show premature SCN, which, in turn, sends neuro-endocrine signals ageing in many tissues. For example, circadian that result in synchronisation of peripheral tissue disruption of Bmal1 led to muscle loss and sarcopenia clocks. The molecular mechanism that generates cell- (Andrews et al. 2010), disrupted cartilage formation autonomous, self-sustained circadian rhythms is gov- (Dudek et al. 2016), bone loss and other features of erned by a network of auto-regulatory feedback loops premature ageing (Kondratov et al. 2006). This of transcription/translation that drive circadian expres- showed that genetic disruption of the circadian clock sion patterns of genes, proteins and metabolites within not only leads to circadian arrhythmia, but also each tissue (Reppert and Weaver 2002). In mammals, degenerative changes in many tissues that are associ- this is carried out by the primary feedback loop which ated with advanced age. Future work will reveal how includes the basic-helix-loop-helix transcription fac- much of tissue degeneration resulting from Bmal1 tors CLOCK (Circadian Locomotor Output Cycles deficiency is caused by impaired Bmal1-dependent Kaput) and BMAL (also known as ARNTL, Aryl stem cell homeostasis, which may be responsible for hydrocarbon Receptor Nuclear Translocator-Like pro- some of the age-related changes seen in various tissue tein 1), which form the positive arm of the molecular systems. clock. When these two proteins heterodimerise, they The link between circadian disruption and adult are able to bind to cis-regulatory enhancer sequences stem cell function during ageing has been investigated called E-boxes on target gene promoters, and initiate recently by comparing the clock dynamics in epider- transcription of numerous genes (King et al. 1997; mal and muscle stem cells isolated from adult and old Gekakis et al. 1998). Target genes include core clock mice (Solanas et al. 2017). Unexpectedly, the authors components such as Period (Per1, Per2 and Per3) and demonstrated that adult stem cells from aged mice Cryptochrome (Cry1 and Cry2) as well as numerous (C 18 months) retained circadian rhythms and that the clock-controlled genes (CCGs). PER and CRY pro- core clock machinery of the epidermal and muscle teins then heterodimerise and translocate to the stem cells remained robustly rhythmic. However, it nucleus. They form a negative arm of the feedback was shown that there was an extensive reprogramming loop, and repress target gene expression, including of the oscillating transcriptome in the aged stem cells, their own transcription, by inhibiting the CLOCK:- switching from homeostatic genes to genes involved BMAL complex (Kume et al. 1999; Shearman et al. in tissue-specific stresses, for example DNA damage 2000). The CLOCK:BMAL heterodimer also induces or autophagy. It was concluded that physiological a stabilising regulatory loop by activating the tran- tissue ageing was associated with the rewiring of stem scription of Retinoic Acid-Related (RAR) orphan cell’s diurnally timed functions, rather than with the nuclear receptors, Rev-erb (also known as Nr1d1, arrhythmia. The former is hypothesized to be switched Nuclear Receptor subfamily 1, group D, member 1) on in older organisms in order to adapt to metabolic and Ror (also known as Nr1f1, Nuclear Receptor cues and tissue-specific age-related traits. This age- subfamily 1, group F, member 1). These bind to associated rewiring of the oscillatory diurnal tran- retinoic acid-related orphan receptor response ele- scriptome was significantly rescued in old mice by ments (ROREs), which are present in many clock- long-term caloric restriction (CR), known to reverse controlled gene promoters as well as the core clock the effects of ageing. As CR diet is known to uncouple gene Bmal. REV-ERB represses transcription of Bmal, the cycling of peripheral tissues from the SCN, this whereas ROR activates it (Guillaumond et al. 2005). rewiring may be driven by the molecular changes in These auto-regulatory loops constitute a molecular the SCN. clock machinery and take approximately 24 h to The role of circadian clock genes in stem cell complete a cycle. A diagram depicting the circadian function has also been investigated in ClockD19 mutant system organisation in mammals and the components mouse model with inactive BMAL1/CLOCK tran- of the molecular clock are depicted in Fig. 2. scriptional complex (Yang et al. 2017). It was shown that mammospheres arising from mammary adult stem 123 Biogerontology (2018) 19:497–517 501

Fig. 2 The circadian system organisation and the molecular primary and stabilising feedback loops, which regulate core clock. Light enters the retina via photoreceptor cells and is clock genes within each loop and numerous target genes in each transduced to the ‘master pacemaker’, the suprachiasmatic tissue (clock-controlled genes, CCGs), leading to synchronisa- nucleus (SCN), in the anterior hypothalamus of the brain. The tion of tissue-specific cellular functions (modified from Rogers SCN relays signals to the ‘peripheral tissue clocks’ throughout et al. (2018) with persmission from BioMedicine) the body. At a molecular level, circadian clocks are regulated via cell progenitors demonstrated rhythmic PER2::luc regeneration. Despite the promising advances made oscillations, which were dampened in the mutant using ASCs in tissue engineering and regenerative mice. Importantly, the ability of the ClockD19 cells to medicine, challenges remain due to diminished tissue form mammospheres was considerably reduced, regeneration seen with ageing when either utilising showing that mice containing genetically disrupted stem cells from old donors or treating an older patient. clocks have impaired stem cell function and renewal. Upon ageing, ASCs exhibit reduced proliferation and This further supports the hypothesis that the age- differentiation which are thought to contribute to associated changes seen in mouse models with genet- tissue deterioration, due to a decline in cell function ically disrupted clocks may be driven by the clock and/or decreased numbers with age (Boyle et al. dysfunction within tissue-specific stem cells. 2007). As ASCs have key role in the maintenance of several organs and tissues, any decrease in their number and/or function can seriously compromise the The implications of ageing on stem cell self- maintenance of tissues and contribute to a number of renewal, proliferation and differentiation age-related phenotypes. For example, studies have shown that cell-extrinsic changes contribute to a One physiological process that has been implicated in decline in stem cell abilities to repair damaged tissues the loss of stem cell homeostasis with age, and is under with age in muscle progenitor cells (Conboy et al. the control of circadian rhythms, relates to tissue 2005).

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The age-associated phenotype in ASCs has pre- lineage is determined by the activation of phenotype- dominantly been studied in human mesenchymal stem specific transcription factors, such as the adipocyte cells (MSCs). Morphologically, old MSCs appear specific PPAR-c2 (Tontonoz et al. 1994) or the larger and more flattened when they reach approxi- osteoblast specific RUNX2/CBFA-1 (Ducy et al. mately 40 population doublings and stop proliferating 1997). Interestingly, it has been shown that despite (Bruder et al. 1997). These age-related changes are increased markers of senescence in MSCs isolated associated with cellular senescence in vitro. The cells from older animals, aged MSCs and ADSCs retain do not only appear larger in size, but show increased their differentiation potential into particular cell fates spreading and display more podia (Mauney et al. such as into Schwann cells (Mantovani et al. 2012). 2004), as well as produce more actin stress fibres Similarly, it was documented that the endothelial (Stenderup et al. 2001). Furthermore, with each differentiation potential of MSCs does not change passage, the MSCs experience a shortening of their with age. However, research by Fafia´n-Labora et al. telomeres. As MSCs from younger donors have longer (2015) showed, in contrast, that MSCs isolated from telomeres, they can expand over many population older rats exhibited a significantly lower differentia- doublings in vitro, proliferate faster and express tion potential than those from younger rats, when pluripotency markers such as Oct-4, Nanog, Rex-1, induced to differentiate into the osteogenic, chrondro- SSEA-3, SSEA-4, Tra-1-60, and Tra-1-81 (Guillot genic or adipogenic cell fates (Fafia´n-Labora et al. et al. 2007). Furthermore, chronological age has been 2015). The authors also reported that the MSCs shown to influence the proliferation rate of ASCs in isolated from the older group of rats exhibited rodents (Fafia´n-Labora et al. 2015). MSCs isolated significantly lower amounts of Nanog, implicating from older donors vary in their expression of prolif- that MSCs from older donors have a lower pluripo- eration marker Ki67, with the reduction in Ki67 tency potential. It was also demonstrated that the corresponding to lower proliferation rates whilst metabolic profiles significantly differed between these increases seen in self-renewal marker CD117 corre- different age groups. The authors carried out iTRAQ spond to higher cell numbers. analysis to compare global profile of proteins from Moreover, ASCs harvested from older donors show MSCs of rat bone marrow at different ages and that the frequency of MSCs in bone marrow is discovered increases in metabolic proteins including significantly lower than in young donors (Tokalov lactate dehydrogenase in MSCs from adult rats, which et al. 2007). Using methods such as flow cytometry to suggested increased rates of glycolysis. This was determine the proportions of cells from different cell further supported by differences observed in the lineages within bone marrow isolated from rats of pentose phosphate pathway activity, whereby different ages, it has been demonstrated that bone decreases in glucose 6 phosphate dehydrogenase marrow consists of three main populations of nucle- activity were seen in the pre-pubertal group whilst ated cells; polynuclear cells (PNCs), megakaryocytic increases were observed in the adult group. cells (MKCs) and mononuclear cells (MNCs), and the Furthermore, a study by Han et al. (2012) sought to proportions of these populations differs with age. ameliorate these age-related changes seen in MSCs to During ageing, an increase in PNCs, a decrease in improve decreased proliferative capacity and myo- MNCs and a limited change in the relative number of genic differentiation potential with age (Han et al. MKCs was observed. Within the CD90 ? MNC 2012). To combat this, the authors ectopically population, the number of MSCs significantly expressed the pluripotency marker Nanog using decreased with age due to a decrease in the maximal lentiviral transduction in BM-MSCs from neonatal lifespan of these cells. and adult donors. They discovered that Nanog re- Upon appropriate stimulation, MSCs give rise to a expression did indeed ameliorate reductions in prolif- number of different mesenchymal cell types, most eration and myogenic differentiation with age. Several frequently undergoing osteogenesis, adipogenesis, signalling pathways that mediate these changes were chondrogenesis or myogenesis. These distinct cellular identified, including the PPAR signalling pathway fates are defined by their particular patterns of gene which was significantly altered in BM-MSCs upon expression. When MSCs differentiate, they switch Nanog expression, with both adipogenic genes CEBPa from one pattern of gene expression to another; the and PPARc becoming downregulated. The 123 Biogerontology (2018) 19:497–517 503 differentiation of BM-MSCs into smooth muscle cells alterations and increased the osteogenic potential of was also enhanced by Nanog expression, as demon- old BM-MSCs (Mantovani et al. 2012). Overall, strated by increased contractility, myogenic function understanding the mechanisms that underlie the age- and an increased expression of smooth muscle cell ing processes within ASCs is vital both in terms of markers such as smoothelin, SM22 and caldesmon ameliorating the age-related tissue deterioration, but (Han et al. 2012). This research suggested that the also for selecting the appropriate biological age of ectopic expression of Nanog may rescue age-mediated stem cell donors and designing future stem cell decline in BM-MSC functions, which could allow for therapies for older patients. the use of BM-MSCs from older donors in regener- ative medicine. Osteogenic progenitors also show a reduced capac- Circadian clocks as a novel mechanism ity for self-renewal in vivo with age (Bellows et al. for temporal control of stem cell function 2003). Indeed, there is an increased number of adipocytes in the old bone marrow and a decreased A recent field of investigation has shown that the clock number of bone-forming osteoblasts, accompanied by genes can directly influence adult stem cell activation reductions in bone mass. This reduction in osteogenic and differentiation, within their tissue-specific niches potential and acquired adipogenic potential with age is (Brown 2014; Aguilar-Arnal and Sassone-Corsi 2011; referred to as an ‘adipogenic switch’ (Ross et al. Plikus et al. 2015). The core circadian clock genes, 2000). Research carried out by Moerman et al. (2004) Per1, Per2, Bmal1, Cry1, Clock, and Rev-erba, were showed that bone marrow aspirates of old mice gave first characterised as actively cycling in mouse HSCs rise to fewer osteoblastic colonies and more adipocytic using a combination of cell sorting by high-speed flow colonies, when compared to adult mice. From this, cytometry and gene expression analyses (Tsinka- they concluded that ageing alters the differentiation lovsky et al. 2005). The circadian clock genes are potential of MSCs, leading to cells being more likely well documented to be expressed in an oscillatory adipogenic than osteogenic. Using a PPAR-c2 agonist, manner in murine adipose tissue, following which they rosiglitazone, the authors demonstrated that sensitivity were also investigated in human subcutaneous adi- to PPAR-c is increased in the old bone marrow, and pose-derived stem cells (Wu et al. 2007). Here, cells that TGF-b/BMP signalling pathways are altered with were synchronised in vitro with synthetic glucocorti- age (Moerman et al. 2004). In addition, Gharibi et al. coid dexamethasone, PPAR- c2 agonist rosiglitazone, (2014) sought to ameliorate the reductions in osteo- or 30% foetal bovine serum, and total RNA collected genesis seen in vitro in MSCs with age (Gharibi et al. every 4 h over a 48 h period. The authors reported that 2014). To do this, the authors demonstrated that differentiated adipocytes were more readily respon- blocking AKT/mTOR pathway prevented the devel- sive to clock synchronisation than undifferentiated opment of this age-related phenotype, maintained the pre-adipocyte precursors, but the period of clock gene MSC morphology and enhanced proliferation capac- oscillations were longer in differentiated adipocytes, ity, matching those seen in early passage MSCs. MSCs validating the use of ADSCs as in in vitro adult stem cultured with inhibitors of AKT and/or mTOR also cell model for the analysis of circadian rhythms (Wu maintained their osteogenic potential. It was specu- et al. 2007). In MSCs, Wu et al. (2008) reported the lated that these effects may be influenced by the presence of the core circadian transcriptional machin- expression of pluripotency genes such as Nanog and ery in both murine and human primary BM-MSCs, and Oct-4 and due to a reduction in reactive oxygen when exposed to the synchronising effects of the species production (Gharibi et al. 2014). Other synthetic glucocorticoid, dexamethasone, BM-MSCs research has shown that growing BM-MSCs on certain showed oscillating expression of the mRNAs encod- biomaterials preserved age-compromised functions, ing Bmal1, Per3, Albumin D Binding Protein (Dbp), maintained the differentiation potential and enhanced Rev-erba and Rev-erbb (Huang et al. 2009). Further- proliferation capacity. BM-MSCs were grown on more, circadian oscillations were also elicited when denatured collagen matrices which significantly influ- BM-MSCs and ADSCs were exposed to serum shock enced the protective stress responses and proliferation and cAMP analogs (Huang et al. 2009). The circadian capacity ex vivo, reduced the rate of morphological mechanisms that have been recently used to 123 504 Biogerontology (2018) 19:497–517

Table 1 The Circadian Synchronisation Mechanisms investigated in Adult Stem Cells Entrainment mechanism References Adult stem cell type cAMP agonists (forskolin) Huang et al. (2009) BM-MSCs, ADSCs Glucocorticoids (dexamethazone) Wu et al. (2007, 2008) BM-MSCs Growth factors (serum shock) Huang et al. (2009) BM-MSCs, ADSCss Temperature O’Neill and Reddy (2011) RBCs Mechanical stretch Simoni et al. (2014) Drosophila Rogers et al. (2017) Melanogaster BM-MSCs, ADSCs, DPSCs Biomaterials Mengatto et al. (2011) Mice Hassan et al. (2017) BM-MSCs

synchronise adult stem cells in vitro can be found in murine model of acute myeloid leukaemia (AML) Table 1, along with rhythmic temperature cycles, (Puram et al. 2016). It was demonstrated that Clock which have been used to synchronise human red blood and Bmal1 were required for the growth of AML cells cells (RBCs) (O’Neill and Reddy 2011). both in vitro and in vivo, and that the disruption of There has been a substantial amount of evidence canonical circadian components led to anti-leukemic that suggests that not only do ASCs express the effects. RNA interference screens were also used to functional core circadian machinery, but that circadian examine the effects of DNA damage and ageing on the clocks have important role in a variety of tissue maintenance of HSCs (Wang et al. 2016). It was homeostatic functions thus influencing the activation discovered that Per2 is activated in lymphoid-biased of stem and progenitor cells (Gimble et al. 2009; HSCs (as opposed to myeloid-biased HSCs) and, in Weger et al. 2017). Circulating HSCs and their hematopoietic cells, wherein it stimulates DNA dam- progenitors in the bloodstream have been shown to age responses and p53-dependent apoptosis. There- exhibit robust circadian oscillations in light/dark fore, Per2 has been identified as a negative regulator entrained animals (Me´ndez-Ferrer et al. 2008). Here, of lymphoid-biased HSCs, immune function and it has been experimentally evidenced that the release lymphopoiesis. Another core clock gene that has been of HSCs into the bloodstream is cyclical, along with implied in cancer stem cells is Per3. Per3 has been the rhythmic expression of C-X-C motif chemokine 12 shown to have an important role in colorectal cancer, (Cxcl12), both of which are regulated by the core being downregulated in colorectal cancer stem cells molecular clock through rhythmic noradrenaline (Zhang et al. 2017). As Per3 has been reported to have secretion. This implies that the clock-driven release a critical role in colorectal cancer stem cells pluripo- of HSCs is stimulated by the CNS during the animal’s tency, it may be a promising gene for targeting cancer resting phase and can promote the tissue regeneration stem cells. Furthermore, circadian rhythms have been and regulate the function of a hematopoietic stem cell linked to tumour cell proliferation by regulating iron niche. metabolism; iron is essential for DNA synthesis and Consequently, any disturbances in this temporal therefore critical in the enhanced rates of proliferation coordination have been implicated in a variety of seen in tumours (Okazaki et al. 2016). Circadian pathologies including premature ageing and cancer. variations in DNA synthesis and proliferation are seen Indeed, recent studies have implicated circadian in tumour cells, and 24-h rhythms can be observed in rhythm disruption in an increased susceptibility to iron regulatory protein 2 (IRP2). IRP2 regulates the cancer development in all major organ systems (Fu 24 h rhythm in transferrin receptor 1 mRNA post- and Kettner 2013). Research by Puram et al. (2016) transcriptionally, and Irp2 is promoted by BMAL1:- utilised a series of in vivo RNA interference screens to CLOCK heterodimers, demonstrating a role for the identify which transcription factors influenced a

123 Biogerontology (2018) 19:497–517 505 circadian clock in tumour cell stem proliferation by synthesis in proliferating stem cells, most likely as a regulating iron metabolism. protective mechanism to prevent genotoxicity. Dis- ruption of this clock-controlled mechanism in stem cells may therefore contribute to stem cell dysfunction The circadian rhythm regulates adult stem cell and have long-term consequences for tissue home- activity at a multi-cellular level ostasis. Further work in hair follicle cycling has shown that prominent daily mitotic rhythms are generated by Recent data has demonstrated that the involvement of peripheral circadian clock within epithelial matrix circadian clocks in the regulation of adult stem cell cells (Plikus et al. 2013), which results in the hair activity is not only cell-specific, but, remarkably, can growing faster in the morning than evening and also act at the cell population level. In a study by therefore being exposed to higher exposure to geno- Janich et al. (2011), it was shown that the circadian toxic stress at certain times of the day. Researchers clock may have a role in regulating the activation of exposed wild-type mice to c-radiation in the morning coexisting epidermal stem cell populations, which are (mitotic peak) versus the evening (when there is in different phases, in order to balance hair growth and minimal hair loss), and reported that the diurnal radio- renewal (Janich et al. 2011). The authors noted that the protective effect is lost in clock mutant mice. The genes regulating niche dormancy, activation and circadian clock was demonstrated to coordinate differentiation contained several putative BMAL1/ genotoxic stress responses with cell cycle progression CLOCK-binding sites, as revealed by gene promoter by influencing the Cdc2/Cyclin B-mediated G2/M analysis. These key epidermal homeostasis genes checkpoint. Further research demonstrating the links included WNT signalling factors, TGF-b regulators between various mammalian peripheral tissue clocks and modulators of BMP and NOTCH signalling and downstream effects on tissue-specific functions, pathways. Chromatin immunoprecipitation (ChIP) including liver, pancreas, adipose, skeletal muscle, assays confirmed the binding of BMAL1/CLOCK to brain, intestine, hematopoietic and immune system, these gene promoters in adult tail epidermis, and that skin and cartilage, has been reviewed in detail (Janich the binding of BMAL1 to these target gene promoters et al. 2014). was rhythmic. Therefore, the molecular clock gener- In contrast to ASCs, the circadian transcriptional ates cell populations that show heterogeneous machinery does not seem to oscillate in ESCs, when responses to external factors, by modulating the analysed using real-time bioluminescent imaging expression of stem cell regulatory genes in an systems (Yagita et al. 2010). However, upon differ- oscillatory manner. Furthermore, the deletion of entiation in vitro, a molecular clock oscillations Bmal1 led to circadian arrhythmia, decreased expres- become strongly induced, which can be reversed if sion of WNT-related genes and TGF-b inhibitors, and the differentiated cells are reprogrammed into induced caused a progressive accumulation of dormant stem pluripotent stem cells (IPSCs) using the four pluripo- cells and premature epidermal ageing. In contrast, tency factors Oct3/4, Sox2, Klf4, and c-Myc (Paulose deleting the negative clock loop components Per1/2, et al. 2012). This suggests that formation of the resulted in progressive depletion of dormant stem circadian molecular oscillator is dependent on an cells, which may have implications for cancer. intrinsic program that occurs during cellular stem cell A subsequent study using human keratinocyte differentiation. When ESCs are maintained in a progenitors showed that these cells responded better pluripotent state in culture, it has been discovered to several differentiation cues at certain times of the that they express a self-sustained rhythm in glucose day (Janich et al. 2013). Interestingly, genes encoding uptake that is not coincident with clock gene oscilla- key proliferation or differentiation proteins were tions, and this rhythm is paralleled by rhythmic expressed at different times of the day. For example, glucose transporter mRNA expression, indicating that DNA replication and cell division pathways were circadian rhythms in metabolism emerge earlier than highly represented in the evening, whilst differentia- clock gene expression rhythms (Paulose et al. 2012). tion pathways predominated in the morning. More- When stem cells become differentiated, however, over, the circadian clock coordinated the activities of circadian patterns in clock gene expression can be glycolysis and oxidative phosphorylation with DNA observed, and the glucose utilization rhythm becomes 123 506 Biogerontology (2018) 19:497–517 enhanced in amplitude, providing the evidence of a proportion of stem cells in S phase (when DNA circadian clock in differentiated stem cells. Further synthesis occurs) (Stringari et al. 2015). This temporal experiments carried out by Lu et al. (2016) have segregation of metabolic processes from stem cell demonstrated that when Clock is knocked out entirely proliferation is thought to act as a protective mecha- using CRISPR/CAS9-mediated genetic editing tech- nism against genotoxicity. niques in mouse ESCs, there was no influence on the cellular pluripotent state, but mESCs did exhibit a decreased proliferation rate and an increased apopto- The molecular clock exerts essential regulation sis. Interestingly, clock gene rhythms failed to develop of stem cell differentiation fate in these mESCs following differentiation, suggesting that Clock may be critical in mESC differentiation (Lu Adipogenesis et al. 2016). These findings have been supported by research in mouse embryonic hearts and ESCs which In addition to their role in stem cell activation, demonstrated a role for the posttranscriptional regu- circadian rhythms have also been extensively linked lation of Clock in development of molecular clock to stem cell proliferation and differentiation. It is well oscillations in differentiating stem cells. Indeed, the established that Bmal1 is involved in the regulation of appearance of CLOCK protein during ESC differen- adipogenesis and lipid metabolism in mature adipo- tiation coincides with the emergence of molecular cytes. When 3T3-L1 cells are subjected to adipogenic clock oscillations and Dicer/Dgcr8-mediated post- differentiation, the level of Bmal1 mRNA increases transcriptional regulation of CLOCK protein (Ume- and it is highly expressed in differentiated adipocytes mura et al. 2017), highlighting the importance of (Guo et al. 2012). Furthermore, mouse embryonic CLOCK in the establishment of circadian clock fibroblasts (MEFs) from Bmal1-deficient mice as well oscillations during embryonic stem cell as 3T3-L1 cells with Bmal1 knock-down fail to differentiation. differentiate into adipocytes. Interestingly, when Mechanistically, it has been shown that expressing BMAL1 is overexpressed with adenoviral gene trans- both transcription factor c-Myc and ablation of DNA fer, this ability is restored and cells can accumulate methyltransferase 1 (Dnmt1) leads to disruption in the lipids and express adipocyte-related genes, such as establishment of the molecular clock oscillations in PPARc2. The promotor activity of these adipogenic differentiating mouse ESCs. It has been reported that, genes is stimulated in a BMAL1-dependent manner, when there is a failure of clock oscillation develop- and the expression of adipogenic factors PPARc2 and ment, an increase in Kpna2 (Importin-a2) and altered adipocyte fatty acid binding protein (AP2) show clear subcellular PERIOD protein localization can be circadian rhythms in murine adipose tissue (Guo et al. observed; therefore differentiation-coupled transcrip- 2012). Taken together, these results suggest that tion of specific genes may regulate circadian clock BMAL1 is an important factor in adipogenesis development in mouse ESCs (Umemura et al. 2014). regulation. Furthermore, ESCs have immature mitochondria, are More recently, it has been shown that Bmal1 reliant on glycolysis for fuel and have no discernible disruption in vivo actually leads to increased adipo- rhythms, compared to differentiated stem cells which genesis, adipocyte hypertrophy and obesity in global have mature mitochondria, acquire oxidative respira- Bmal1 KO mice (Shimba et al. 2005). Here, it has been tion and show clear rhythms, linking redox regulation uncovered that Bmal1 deletion leads to down-regula- to stem cell differentiation and the development of tion of genes in the canonical WNT signalling circadian clocks. Indeed, clear redox oscillations can pathway, which are known to suppress adipogenesis. be imaged in proliferating epidermal stem cells, The gene promoters of several of these WNT- demonstrating the role for circadian clocks in regu- regulated genes, including Wnt10a, b-catenin, Fzd5, lating metabolism in adult stem cells (Stringari et al. Dvl2 and Tcf3 displayed BMAL1 occupancy. Simi- 2015). The adult stem cell clock coordinates the larly, Bmal1 knock down led to attenuation of WNT activities of DNA synthesis with glycolysis and signalling pathway, whilst BMAL1 overexpression oxidative phosphorylation, whereby increased glycol- led to opposite effects. Stabilising b-catenin through ysis is found during the night, along with a higher WNT ligand administration or GSK-3b inhibition 123 Biogerontology (2018) 19:497–517 507 ameliorated the decreased WNT signalling and res- that mPer2 provides a functional link by influencing cued inhibition of adipogenesis induced by Bmal1 the early cellular events that lead to post-mitotic knock-down. Taken together, this study offered a granule cell production underlying adult hippocampal mechanistic links between Bmal1 disruption, altered neurogenesis (Borgs et al. 2009). In the lateral adipogenesis and development of obesity in mice subventricular zone (SVZ), the area in the brain where (Shimba et al. 2005). Another clock gene implied in NPCs persist and postnatal neurogenesis occurs, the adipose cell differentiation is Rev-erba (NR1D1), expression pattern of clock genes changes following which has been shown to be a key regulator of brown the onset of differentiation, and Bmal1 begins to adipose tissue development (Nam et al. 2015). As Rev- oscillate endogenously. If Clock or Bmal1 were erba promotes brown adipogenesis, genetic ablation silenced using RNA interference, the percentage of of Rev-erba impairs embryonic and neonatal brown fat neuronal marker Map2-positive cells decreased as formation in mice, by disrupting brown adipocyte well as the expression level of neurogenic transcrip- lineage commitment and terminal differentiation. By tion factors such as NeuroD1 (Kimiwada et al. 2009). pharmacologically activating REV-ERBa activity, A study recently published by Akle et al. (2017) brown adipocyte differentiation can be promoted, as showed that all neurogenic niches studied in an adult REV-ERBa represses key components of the TGF-b diurnal vertebrate, the zebrafish, including the dorsal cascade, which, in turn, inhibits brown fat telencephalon, habenula, preoptic area, hypothalamus development. and cerebellum, showed circadian modulation of cell cycle progression that involved the use of both niche- Neurogenesis specific and systemic factors (Akle et al. 2017).

Adult neurogenesis, which generates both new neu- Osteogenesis rons and glia, is regulated by circadian rhythms. When neurosphere cultures prepared from the dentate gyrus The circadian clock has also been implicated in bone in the brain are isolated from mPer1::luc clock homeostasis. Bmal1 KO mice display low bone mass reporter mice, it was apparent that circadian mPer1 phenotype which worsens over lifespan. These mice gene rhythms can be observed in neurospheres where have decreases in cortical and trabecular bone volume neurogenesis was induced, but not in those neuro- and a lower bone mineral density when visualised spheres maintained in the stem cell state (Malik et al. using micro-computed tomography (Samsa et al. 2015). In addition, neurospheres used from both 2016). Bmal1 deficiency in vivo has been shown to Bmal1 KO as well as Cry1/2 KO mice, another genetic result in a decreased number of active osteocytes and model of circadian disruption, showed that circadian osteoblasts, and isolated BM-MSCs displayed a rhythms are not required for neurosphere induction reduced osteoblastic differentiation capacity, likely in vitro. However, the absence of these clock compo- contributing to the observed reduction in osteoblast nents did restrict neurosphere growth, neuronal fate and osteocyte numbers (Samsa et al. 2016). Another commitment and increased cell death. Quiescent clock gene implicated in BM-MSC proliferation and neural progenitor cells (QNPs) in the subgranular osteogenesis is Rev-erba. It has been demonstrated zone (SGZ) of the adult hippocampus also express that Rev-erba expression decreases during osteogen- components of the molecular clock and proliferate in a esis. Rev-erba overexpression led to inhibition of BM- rhythmic manner (Bouchard-Cannon et al. 2013). MSC proliferation and osteogenic differentiation, Here, the clock proteins PER2 and BMAL1 are which were partially rescued by activating Wnt/b- essential for the control of neurogenesis. The circadian catenin signalling via exogenous Wnt3a ligand admin- clock is crucial in timing the entry and exit of the istration (He et al. 2014). This suggests that increased QNPs into the cell cycle and, without these clock Rev-erba levels could promote BM-MSC ageing and components, the quiescent state achieved during negatively regulate osteogenesis with age, which neuronal differentiation is delayed. warrants further investigation. Moreover, mPer2 is also expressed by neural stem/ progenitor cells (NPCs) differentiating to mature neurons in the dentate gyrus. It has been postulated 123 508 Biogerontology (2018) 19:497–517

Chrondrogenesis lower satellite cell expansion, which leads to defective regenerative responses. These mice exhibit a nearly It has also been documented that Bmal1 expression is non-existent induction of Pax7, a satellite cell marker. decreased in human cartilage from osteoarthritic The satellite cell-derived myoblasts isolated from patients and aged mouse cartilage (Dudek et al. Bmal1 KO mice demonstrate reduced growth and 2016). By ablating Bmal1 expression in mouse proliferation ex vivo, underscoring the role of Bmal1 chondrocytes specifically, this led to progressive in both muscle maintenance and repair (Sun et al. degeneration of articular cartilage, most likely as a 2014). result of a number of altered molecular pathways that Bmal1 targets. Indeed, Bmal1 ablation in cartilage led Angiogenesis to altered TGFb pathway associated with an altered ratio in levels of phosphorylated SMAD2/3 versus Circadian clock protein PER2 is thought to be a key phosphorylated SMAD1/5. Moreover, altered factor in maintaining endothelial progenitor cell (EPL) NFATc2 transcription factor pathway was observed, function during angiogenesis. PER2 is abundantly together with reduced expression of matrix related expressed in early EPCs, whilst EPCs from Per2-/- - genes Sox9, Acan, and Col2a1, linking the circadian mice demonstrate impaired proliferation, adhesion, clock to the maintenance and repair of cartilage. migration and tube formation due to inhibitions of both PI3K/Akt/FoxO signalling and protein levels of Myogenesis C-X-C chemokine receptor type 4 (CXCR4). Interest- ingly, the negative proliferation effects of Per2 Important role for Bmal1 has been demonstrated deficiency can be rescued by activating PI3K/Akt/ regarding myogenesis. Bmal1 Is highly expressed in FoxO signalling. Indeed, PER2 and CXCR4 directly skeletal muscle and is thought to regulate myogenic interact in EPCs, showing that PER2 is essential in differentiation via direct transcriptional activation of maintaining early EPC function (Al Mheid et al. canonical Wnt signalling pathway components (Chat- 2014). In humans, circulating progenitor cells and terjee et al. 2013, 2015). Moreover, it has been shown their proangiogenic activity also exhibit circadian that a master regulator of myogenesis, MyoD, displays variations. They show unfavourable profiles in the cyclical mRNA and protein levels, and is a direct morning which coincides with prevalence of cardio- target of CLOCK and BMAL1. Bmal1 KO and vascular events, directly influenced by the endogenous ClockD19 mouse models show reductions in the total circadian clock (Bhatwadekar et al. 2017). When muscle mass and maximal force including reduced Bmal1 is conditionally deleted in endothelium and mitochondrial volume, demonstrating the importance hematopoietic cells specifically, cellular responses to of CLOCK and BMAL1 in skeletal muscle structure microvascular and macrovascular injuries are exag- and function (Andrews et al. 2010). Similarly, when gerated (Dierickx et al. 2017), highlighting the Bmal1 is knocked down in myoblasts, this led to importance of circadian rhythms in maintaining vas- impaired myogenic differentiation and decreased cular homeostasis. expression of key myogenic regulatory factors includ- ing Myf5, Mrf4 and Myogenin as well as Myosin Heavy Other tissue-specific cell differentiation Chain 3 (MHC3). Overexpression of Bmal1 in C2C12 myoblasts conversely led to accelerated myogenesis In the cardiac muscle, circadian rhythms regulate and attenuation of Wnt signalling, indicating that cardiac physiology and metabolism and are known to Bmal1 is required for myoblast differentiation (Chat- determine outcomes of ischemic stress (Van Laake terjee et al. 2013) Direct binding of BMAL1 to gene et al. 2018). Human ESCs progressively oscillate promoters coding for canonical Wnt pathway genes following directed cardiac differentiation. Further- has been demonstrated in line with circadian oscilla- more, a number of clock-controlled output genes in the tions of several Wnt pathway components (Chatterjee heart have been identified as an oscillatory network of et al. 2015). Bmal1 can also influence skeletal muscle stress-related genes, including genes known to play an function through influencing its regeneration process important role in human heart physiology, including (Sun et al. 2014). Bmal1 KO mice display significantly Pln, Kcne4, Tspo, Cav1 and Rgs2 (Dierickx et al. 123 Biogerontology (2018) 19:497–517 509

Fig. 3 Summary of the Common Changes seen with Ageing and Circadian Clock Disruption

2017). Stem cell antigen 1-positive (SCA1?) cells, The impact of the circadian rhythms on stem cell which can be detected in the heart, have been shown to homeostasis and cell cycle progression possess a molecular clock and exhibit circadian oscillations that control downstream cellular functions Research by Boucher et al. (2016) has demonstrated (Du Pre´ et al. 2017). These findings demonstrate the the effects of the clock genes on MSC differentiation, importance of circadian regulation in cardiovascular migration and cell cycle regulation. They showed that functions. knock down of Clock or Per2 led to inhibition of Intestinal stem cells (ISCs) are critical in determin- adipocyte differentiation, while osteoblastic differen- ing how the intestine regenerates in order to replace tiation was unaffected. Cell migration was decreased dying cells. The PER transcription factor has been in Per2 KD cells together with altered hMSC cell discovered to be essential in intestinal regeneration, cycle stage distribution. This was in line with observed and numerous gene transcripts that are regulated by changes in cyclin expression profiles including sig- the circadian clock have been uncovered within nificant decreases in several cell cycle regulators p19, intestinal stem cells, including those involved in stress p27, Cyclin B1 and Cyclin D1 protein levels (Boucher response and regeneration pathways (Karpowicz et al. et al. 2016). This is further evidence that the circadian 2013). Disruption of clock component Per has been clock in stem cells is important in maintaining their shown to lead to arrhythmic ISC divisions, demon- function and properties. strating how diverse roles in stem cells are played by Further research examined the role of the clock in the components of the molecular clock in different cell cycle regulation of hair follicle stem cells peripheral tissues (Karpowicz et al. 2013). A sum- (HFSCs) that reside within the bulge (Zagni et al. mary of tissue phenotypes associated with disrupted 2017). One of the major regulators of the PI3K/AKT circadian rhythms which are commonly found in pathway, PTEN, has a critical role in controlling various tissue systems affected during ageing is shown HFSC number and size, and maintaining the pluripo- in Fig. 3. tent state of stem cells. PTEN and BMAL1 show functional links; when Pten is deregulated, this causes constitutive activation of BMAL1, and BMAL1 is involved in the maintenance of the PTEN-induced

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Table 2 Signalling Pathways Controlled by the Circadian Clock relevant to Adult Stem Cell Function Signalling Role in adult stem References pathways cells

WNT Differentiation Janich et al. (2011), Guo et al. (2012), Chatterjee et al. (2013), Chatterjee et al. (2015) NOTCH Self-renewal Zhang et al. (2017) and Janich et al. (2011) Several factors bound by Bmal1 p53 Apoptosis Yagita et al. (2010) Activated by Per2 Cyclin B Cell cycle Plikus et al. (2013), Boucher et al. (2016) PI3K/AKT Homeostasis/ Sun et al. (2014), Zagni et al. (2017) proliferation TGF-b Homeostasis/ Moerman et al. (2004), Janich et al. (2011) and Plikus et al. (2013) proliferation BMP Proliferation Janich et al. (2011) Rho/ROCK Homeostasis Yang et al. (2017) ROS/NRF2 Homeostasis Kondratov et al. (2006), Kondratov et al. (2009) and Pekovic-Vaughan et al. (2014) phenotype. Short-term and long-term Pten depletion Bmal1 in mice leads to altered redox homeostasis leads to BMAL1 activation, which contributes to with increased accumulation of ROS in several tissues HFSC accumulation. (Kondratov et al. 2006), which can be partially Another important aspect of circadian clock regu- ameliorated with administration of glutathione pre- lation of stem cells relates to the ‘clock-gated’ cell cursor N-acetyl cysteine (NAC) (Kondratov et al. division cycles. Using 3D murine organoids, research- 2009). Moreover, ClockD19 mice show diminished ers have demonstrated Wnt-mediated intercellular levels of antioxidant transcription factor Nrf2 and its coupling between the cell cycle and the circadian target antioxidant genes leading to an increased clock (Matsu-ura et al. 2016). The molecular clock accumulation of protein oxidative damage in the lungs ‘gates’ the existence of cell populations with hetero- with ageing (Pekovic-Vaughan et al. 2014). CLOCK geneous cell cycle times generating self-synchronised, and BMAL1 heterodimer were found to positively 12-h cell division cycles. It is thought that an regulate Nrf2 transcription by temporal control of the intercellular signal linking circadian and cell division E-box element in the Nrf2 gene promoter. NRF2 cycles is established by differentiated cells (Matsu-ura protein, in turn, drives the rhythmic transcription of et al. 2016). A summary of the signalling pathways antioxidant genes via temporal binding to antioxidant that affect stem cell activation, proliferation and response elements (AREs) in several gene promoters differentiation, which are under circadian control, encoding enzymes involved in glutathione synthesis can be found in Table 2. and utilisation. The lack of NRF2-mediated antioxi- Furthermore, circadian clock is implicated in dant defence provides a potential mechanism for the several cellular protective mechanisms that are impor- premature onset of age-related pathologies seen in the tant for stem cell homeostasis such as antioxidant absence of Bmal1 in mice (Pekovic-Vaughan et al. stress responses (Kondratov et al. 2009). Reactive 2014). oxygen species (ROS) are produced as a by-product of cellular metabolism and serve as signalling molecules. However, increased ROS production and/or clearance The effects of circadian rhythms on stem cell results in oxidative stress, leading to oxidative damage biomaterials and tissue engineering to major macromolecules including proteins, lipids and DNA, which is associated with tissue degenera- In regenerative medicine, there is a great need to tion with ageing (Paul et al. 2014; Dickinson and generate mature functional tissues in vitro, especially Chang 2011). Importantly, genetic disruption of given our increasingly ageing society. Therefore, it is

123 Biogerontology (2018) 19:497–517 511 essential to discover effective means to direct differ- modifications (Hassan et al. 2017). When cultured entiation of stem cells into tissue-specific cells in a on such materials, BM-MSCs supressed PER1 expres- controlled manner, which requires appropriate bio- sion and upregulated NPAS2. When further investi- chemical and biophysical signals within cellular gated using Npas2 KO mice, the titanium biomaterial- microenvironments. Biomaterials provide a 3D envi- induced suppression of Per1 was not rescued and the ronment equipped with biological, mechanical and expression of other clock genes Per2, Per3, Bmal1 and chemical cues, which can stimulate cells to proliferate, Clock was not affected, suggesting that the altered differentiate, secrete extracellular matrix and form expression of Per1 was independent of Npas2. The functional tissues (Hwang et al. 2008; Burdick and authors concluded that titanium-based biomaterials Vunjak-Novakovic 2008; Singh and Elisseeff 2010; can influence BM-MSC circadian rhythms, and altered Lutolf et al. 2009; Dawson et al. 2008). Intelligent BM-MSC rhythms may be important factor in deter- biomaterials that can mimic the required physical and mining the rate of titanium-based biomaterial integra- biochemical environments and provide the necessary tion into bone. This exciting area of research signals for stem cell activation and differentiation examining how materials influence the stem cell clock have recently undergone intense research. Many types warrants further research, and the authors of this of biomaterials have been developed, including the use review are optimistic that it will be a very prosperous of natural materials, which consist of extracellular area of research to come. matrix components such as collagen, fibrinogen, The circadian clock has recently been implicated in hyaluronic acid, glycosaminoglycans (GAGs), lami- regenerative medicine as it has been shown to have a nin and hydroxyapatite (HA), as well as synthetic profound effect on the wound healing response in mice materials, such as polymers, ceramics and metals. and humans (Hoyle et al. 2017). Skin wounds in mice There has also been a drive to utilise surface modi- healed faster in the active period than those incurred in fications of biomaterials, including chemical and the rest period ex vivo and in vivo. Using a proteome- biological modifications, so that the differentiation wide screen for rhythmically expressed proteins in of stem cells may be selectively steered down fibroblast cells, the authors uncovered a circadian particular cellular fates. Several articles have regulation of actin, a cytoskeletal protein involved in reviewed in detail the application of biomaterials in cell migration, which is an important aspect in the stem cell differentiation (Dawson et al. 2008; Hwang wound-healing response of fibroblasts and ker- et al. 2008; Burdick and Vunjak-Novakovic 2008; atinocytes (Hoyle et al. 2017). Analysis of a database Singh and Elisseeff 2010; Lutolf et al. 2009). of human burn injuries showed that human burns The circadian rhythms have recently been implied patients who incurred their injuries in the night, i.e. in dental and orthopedic implant integration. In order rest period, healed more slowly than those incurred in to investigate causes of failure in osseo-integration, an the day, i.e. active period. This research highlights the implant failure model under vitamin D deficiency was importance of the circadian regulation of the cellular utilised to identify crucial gene networks that underpin cytoskeleton in modulating wound healing responses this process (Mengatto et al. 2011). Following and underlines the importance of the circadian genome-wide transcriptomic and bioinformatic rhythms in regenerative medicine. molecular pathway analyses, it was reported that the circadian rhythm pathway was among the top molec- ular pathway affected. Npas2 and Bmal1 were upreg- The effects of the rhythmic mechanical cues ulated around the implant and diminished by vitamin on stem cell clocks D deficiency, whereas the Per2 expression pattern showed the opposite trend. It was thus concluded that The circadian clock has a period of approximately, but the circadian rhythms, along with the extracellular not exactly, 24 h. Therefore, it must be reset daily by matrix, may be involved in osseo-integration estab- external cues, known as Zeitgebers. The most common lishment under vitamin D regulation. of these cues is light which, in mammals, entrains In a recent follow up study by Hassan et al. (2017), rhythms in the SCN through retino-hypothalamic the circadian rhythm of BM-MSCs was induced using tract. The SCN relays this temporal information to titanium-based biomaterials with complex surface the rest of the brain and peripheral tissue clocks via 123 512 Biogerontology (2018) 19:497–517 diffusible signals and neuroendocrine factors (Silver human ASCs (Rogers et al. 2017). Here, primary et al. 1996). As the mammalian core body temperature human ASCs from bone marrow, dental pulp and itself oscillates in a circadian manner, this too can act adipose tissues were synchronised using a novel as a Zeitgeber, as was initially shown by subjecting mechanical cell stretch paradigm (12 h ON: 12 h cultured fibroblasts to rhythmic temperature oscilla- OFF cyclical uniaxial stretch for three days) and the tions (Brown et al. 2002). This temperature entrain- expression of core clock genes analysed over two ment was demonstrated to be sufficient to sustain circadian cycles in the absence of rhythmic stimula- circadian rhythmicity in vivo, and abnormal temper- tion. Rhythmic mechanical stimulation was sufficient atures cycles were reported to cause decoupling of to synchronise circadian rhythms in distinct ASCs, peripheral oscillators from the SCN (Brown et al. with differential propensity for mechanical synchro- 2002). Glucocorticoids, which are a class of steroid nisation displayed by ASCs derived from distinct hormones that bind to the glucocorticoid receptor human tissue locations. Interestingly, mechanical (GR) present on almost every vertebrate cell surface strain has also been shown to inhibit adipogenesis in (except the SCN), have also been implicated in MSCs by stimulating a robust b-catenin signal (Sen synchronising peripheral circadian rhythms in human et al. 2008), which is in line with the previous reports and murine ASCs (Balsalobre et al. 2000; Wu et al. showing that Bmal1 influences adipogenesis through 2008). Huang et al. (2009) have demonstrated that b-catenin pathway. Whether BMAL1 has a role in human stem cells have circadian oscillations that can regulating mechano-transduction pathways to influ- be induced by serum shock and cAMP analogues ence adipogenesis is currently unknown and warrants in vitro (Huang et al. 2009), showing that stem cells further investigation. A summary of the circadian can be synchronised using hormones and growth synchronising mechanisms that have been investi- factors. gated in ASCs is presented in Table 1. One emerging entrainment mechanism of circadian A recent study has demonstrated the importance of clocks is mechanical stimulation. Indeed, in the body, cell–matrix interactions for stem cell clocks and different cells in various anatomical locations are discovered that the mammary epithelial clock is subjected to varying amounts of mechanical strain. regulated by the mechanical stiffness of the cellular Published data has demonstrated that a uniaxial strain microenvironment (Yang et al. 2017). The authors between 5 and 15% with a frequency of 1 Hz has demonstrated that genetic disruption of clocks com- notable effects on MSCs both on proliferation and promises the self-renewal ability of the mammary collagen synthesis (Sun et al. 2016). Furthermore, epithelial stem cells, underlining the key link between O’Caerbhaill et al. (2008) highlighted that radial clock genes and mammary stem cell function. Inter- distensions of 5% and frequencies of 1 Hz caused estingly, the authors demonstrated a functional link mechanosensitive effects on stem cells including cell between tissue matrix stiffness with age and the reorientation parallel with direction of flow and altered amplitude changes in clock oscillations. Increased cellular morphologies, highlighting that there is a tissue stiffening with age was shown to suppress the significant cytoskeletal restructuring in mechanically amplitude of the mammary clock oscillations through stimulated MSCs compared to static cells. the tension sensing cell–matrix adhesion molecule, Recent research has also demonstrated that vinculin, and the Rho/ROCK signalling pathway. This mechanical vibrations have the capability of resetting mechano-transduction signalling pathway is, in turn, the clock in Drosophila melanogaster. It has been transduced into the cell to regulate the activity of core shown that rhythmic mechanical stimulation of the clock machinery. In this study, the authors also chordotonal organs can synchronize the Drosophila investigated whether the circadian rhythms in mam- circadian clock (Simoni et al. 2014). Loss-of-function mary tissues isolated from old mice can be restored by mutation in the Period gene led to impaired ability of administering drugs to alter matrix stiffness. ROCK mechanical synchronization, highlighting the impor- pathway inhibitors were used, implicated in matrix tance of a functional clock system for mechanical stiffness regulation, which led to improved amplitude entrainment. Research from our own group has of clock gene oscillations in mammary tissues from recently demonstrated that cyclical mechanical stretch old mice (Yang et al. 2017). Therefore, it was can be used to synchronise circadian rhythms of concluded that tissue stiffening seen with ageing is 123 Biogerontology (2018) 19:497–517 513 thought to suppress the mammary clock in vivo, References providing a mechanism of how ageing disturbs the mammary epithelial stem cell clock through altering Aguilar-Arnal L, Sassone-Corsi P (2011) Stem cells: the clock the stem cell niche. within. Nature 480(7376):185–187 Akle V, Stankiewicz AJ, Kharchenko V, Yu L, Kharchenko PV, Zhdanova IV (2017) Circadian kinetics of cell cycle pro- gression in adult neurogenic niches of a diurnal vertebrate. Summary J Neurosci 37(7):1900–1909 Al Mheid I, Corrigan F, Shirazi F, Veledar E, Li Q, Alexander WR, Taylor WR, Waller EK, Quyyumi AA (2014) Circa- The field of circadian stem cell biology is a dynamic dian variation in vascular function and regenerative area, which has provided us critical insights into the capacity in healthy humans. J Am Heart Assoc temporal control of stem cell function and mainte- 3(3):e000845 nance. Whilst these are exciting developments, there is Andrews JL, Zhang X, McCarthy JJ, McDearmon EL, Horn- berger TA, Russell B, Campbell KS, Arbogast S, Reid MB, much fundamental research that is still needed as our Walker JR, Hogenesch JB (2010) CLOCK and BMAL1 understanding in this crucial area continues. Key regulate MyoD and are necessary for maintenance of aspects to build on over the next few years include the skeletal muscle phenotype and function. Proc Natl Acad bi-directional effects of the biomaterials and biome- Sci 107(44):19090–19095 Balsalobre A, Brown SA, Marcacci L, Tronche F, Kellendonk chanical factors on stem cell clocks. Future research C, Reichardt HM, Schu¨tz G, Schibler U (2000) Resetting of assessing the role of epigenetic factors on stem cell circadian time in peripheral tissues by glucocorticoid sig- clocks, which are well documented to influence both naling. Science 289(5488):2344–2347 circadian rhythms and ASC function, will be of great Becker AJ, McCulloch EA, Till JE (1963) Cytological demon- stration of the clonal nature of spleen colonies derived from importance to the application of circadian biology to transplanted mouse marrow cells. Nature stem cell research. In summary, the invaluable 197(4866):452–454 knowledge pertaining to temporal regulation of stem Bellows CG, Pei W, Jia Y, Heersche JNM (2003) Proliferation, cell physiology and metabolism by tissue-specific differentiation and self-renewal of osteoprogenitors in vertebral cell populations from aged and young female rats. circadian clocks will provide novel insights into the Mech Ageing Dev 124(6):747–757 dynamic processes that change during stem cell Bhatwadekar AD, Beli E, Diao Y, Chen J, Luo Q, Alex A, ageing, and allow appropriate optimisation of smart Caballero S, Dominguez JM II, Salazar TE, Busik JV, biomaterials and mechanical cues essential for steer- Segal MS (2017) Conditional deletion of Bmal1 accentu- ates microvascular and macrovascular injury. Am J Pathol ing stem cells into particular cell fates. Such critical 187(6):1426–1435 findings are essential for future design of novel Borgs L, Beukelaers P, Vandenbosch R, Nguyen L, Moonen G, cellular therapies to ameliorate and/or slow down a Maquet P, Albrecht U, Belachew S, Malgrange B (2009) number of age-related diseases and begin to tackle Period 2 regulates neural stem/progenitor cell proliferation in the adult hippocampus. BMC Neurosci 10(1):30 their prevention. Bouchard-Cannon P, Mendoza-Viveros L, Yuen A, Kærn M, Cheng HYM (2013) The circadian molecular clock regu- Acknowledgements The authors would like to acknowledge lates adult hippocampal neurogenesis by controlling the support from the Analytical Biosciences Group of the Royal timing of cell-cycle entry and exit. Cell Rep 5(4):961–973 Society of Chemistry (EHR and JAH), MRC-ARUK Centre for Boucher H, Vanneaux V, Domet T, Parouchev A, Larghero J Integrated Research on Musculoskeletal Ageing (VPV and (2016) Circadian clock genes modulate human bone mar- JAH), Welcome Trust Institutional Strategic Fund Fellowship row mesenchymal stem cell differentiation, migration and (VPV) and MRC New Investigator Research Grant(VPV). cell cycle. PLoS ONE 11(1):e0146674 Boyle M, Wong C, Rocha M, Jones DL (2007) Decline in self- Open Access This article is distributed under the terms of the renewal factors contributes to aging of the stem cell niche Creative Commons Attribution 4.0 International License (http:// in the Drosophila testis. Cell Stem Cell 1(4):470–478 creativecommons.org/licenses/by/4.0/), which permits unre- Brown SA (2014) Circadian clock-mediated control of stem cell stricted use, distribution, and reproduction in any medium, division and differentiation: beyond night and day. provided you give appropriate credit to the original Development 141(16):3105–3111 author(s) and the source, provide a link to the Creative Com- Brown SA, Zumbrunn G, Fleury-Olela F, Preitner N, Schibler U mons license, and indicate if changes were made. (2002) Rhythms of mammalian body temperature can sustain peripheral circadian clocks. Curr Biol 12(18):1574–1583 Bruder SP, Jaiswal N, Haynesworth SE (1997) Growth kinetics, self-renewal, and the osteogenic potential of purified

123 514 Biogerontology (2018) 19:497–517

human mesenchymal stem cells during extensive subcul- REV-ERB and ROR nuclear receptors. J Biol Rhythm tivation and following cryopreservation. J Cell Biochem 20(5):391–403 64(2):278–294 Guillot PV, Gotherstrom C, Chan J, Kurata H, Fisk NM (2007) Burdick JA, Vunjak-Novakovic G (2008) Engineered Human first-trimester fetal MSC express pluripotency microenvironments for controlled stem cell differentiation. markers and grow faster and have longer telomeres than Tissue Eng Part A 15(2):205–219 adult MSC. Stem Cells 25(3):646–654 Chatterjee S, Nam D, Guo B, Kim JM, Winnier GE, Lee J, Guo B, Chatterjee S, Li L, Kim JM, Lee J, Yechoor VK, Minze Berdeaux R, Yechoor VK, Ma K (2013) Brain and muscle LJ, Hsueh W, Ma K (2012) The clock gene, brain and Arnt-like 1 is a key regulator of myogenesis. J Cell Sci muscle Arnt-like 1, regulates adipogenesis via Wnt sig- 126(10):2213–2224 naling pathway. FASEB J 26(8):3453–3463 Chatterjee S, Yin H, Nam D, Li Y, Ma K (2015) Brain and Han J, Mistriotis P, Lei P, Wang D, Liu S, Andreadis ST (2012) muscle Arnt-like 1 promotes skeletal muscle regeneration Nanog reverses the effects of organismal aging on mes- through satellite cell expansion. Exp Cell Res enchymal stem cell proliferation and myogenic differen- 331(1):200–210 tiation potential. Stem Cells 30(12):2746–2759 Conboy IM, Conboy MJ, Wagers AJ, Girma ER, Weissman IL, Hassan N, McCarville K, Morinaga K, Mengatto CM, Lang- Rando TA (2005) Rejuvenation of aged progenitor cells by felder P, Hokugo A, Tahara Y, Colwell CS, Nishimura I exposure to a young systemic environment. Nature (2017) Titanium biomaterials with complex surfaces 433(7027):760–764 induced aberrant peripheral circadian rhythms in bone Dawson E, Mapili G, Erickson K, Taqvi S, Roy K (2008) Bio- marrow mesenchymal stromal cells. PLoS ONE materials for stem cell differentiation. Adv Drug Deliv Rev 12(8):e0183359 60(2):215–228 He Y, Lin F, Chen Y, Tan Z, Bai D, Zhao Q (2014) Overex- Dickinson BC, Chang CJ (2011) Chemistry and biology of pression of the circadian clock gene Rev-erba affects reactive oxygen species in signalling or stress responses. murine bone mesenchymal stem cell proliferation and Nat Chem Biol 7(8):504 osteogenesis. Stem Cells Dev 24(10):1194–1204 Dierickx P, Vermunt MW, Muraro MJ, Creyghton MP, Hoyle NP, Seinkmane E, Putker M, Feeney KA, Krogager TP, Doevendans PA, van Oudenaarden A, Geijsen N, Van Chesham JE, Bray LK, Thomas JM, Dunn K, Blaikley J, Laake LW (2017) Circadian networks in human embryonic O’Neill JS (2017) Circadian actin dynamics drive rhythmic stem cell-derived cardiomyocytes. EMBO Rep fibroblast mobilization during wound healing. Sci Transl 17:1199–1212 Med 9(415):2774–2775 Du Pre´ BC, Demkes EJ, Feyen DAM, Dierickx P, Crnko S, Kok Huang TS, Grodeland G, Sleire L, Wang MY, Kvalheim G, BJM, Sluijter JPG, Doevendans PA, Vos MA, Van Veen Laerum OD (2009) Induction of circadian rhythm in cul- TAB, Van Laake LW (2017) SCA1 ? cells from the heart tured human mesenchymal stem cells by serum shock and possess a molecular circadian clock and display circadian cAMP analogs in vitro. Chronobiol Int 26(2):242–257 oscillations in cellular functions. Stem Cell Rep Hwang NS, Varghese S, Elisseeff J (2008) Controlled differ- 9(3):762–769 entiation of stem cells. Adv Drug Deliv Rev 60(2):199–214 Ducy P, Zhang R, Geoffroy V, Ridall AL, Karsenty G (1997) Janich P, Pascual G, Merlos-Sua´rez A, Batlle E, Ripperger J, Osf2/Cbfa1: a transcriptional activator of osteoblast dif- Albrecht U, Cheng HYM, Obrietan K, Di Croce L, Benitah ferentiation. Cell 89(5):747–754 SA (2011) The circadian molecular clock creates epider- Dudek M, Gossan N, Yang N, Im HJ, Ruckshanthi JP, Yoshitane mal stem cell heterogeneity. Nature 480(7376):209–214 H, Li X, Jin D, Wang P, Boudiffa M, Bellantuono I (2016) Janich P, Toufighi K, Solanas G, Luis NM, Minkwitz S, Serrano The chondrocyte clock gene Bmal1 controls cartilage L, Lehner B, Benitah SA (2013) Human epidermal stem homeostasis and integrity. J Clin Investig 126(1):365 cell function is regulated by circadian oscillations. Cell Fafia´n-Labora J, Ferna´ndez-Pernas P, Fuentes I, De Toro J, Stem Cell 13(6):745–753 Oreiro N, Sangiao-Alvarellos S, Mateos J, Arufe MC Janich P, Meng QJ, Benitah SA (2014) Circadian control of (2015) Influence of age on rat bone-marrow mesenchymal tissue homeostasis and adult stem cells. Curr Opin Cell stem cells potential. Scientific Reports 5:16765 Biol 31:8–15 Fu L, Kettner NM (2013) The circadian clock in cancer devel- Karpowicz P, Zhang Y, Hogenesch JB, Emery P, Perrimon N opment and therapy. Prog Mol Biol Transl Sci 119:221 (2013) The circadian clock gates the intestinal stem cell Gekakis N, Staknis D, Nguyen HB, Davis FC, Wilsbacher LD, regenerative state. Cell Rep 3(4):996–1004 King DP, Takahashi JS, Weitz CJ (1998) Role of the Kimiwada T, Sakurai M, Ohashi H, Aoki S, Tominaga T, Wada CLOCK protein in the mammalian circadian mechanism. K (2009) Clock genes regulate neurogenic transcription Science 280(5369):1564–1569 factors, including NeuroD1, and the neuronal differentia- Gharibi B, Farzadi S, Ghuman M, Hughes FJ (2014) Inhibition tion of adult neural stem/progenitor cells. Neurochem Int of Akt/mTOR attenuates age-related changes in mes- 54(5):277–285 enchymal stem cells. Stem Cells 32(8):2256–2266 King DP, Zhao Y, Sangoram AM, Wilsbacher LD, Tanaka M, Gimble JM, Floyd ZE, Bunnell BA (2009) The 4th dimension Antoch MP, Steeves TDL, Hotz Viaterna M, Kornhauser and adult stem cells: can timing be everything? J Cell JM, Lowrey P, Turek FW, Takahashi JS (1997) Positional Biochem 107(4):569–578 cloning of the mouse circadian clockgene. Cell Guillaumond F, Dardente H, Gigue`re V, Cermakian N (2005) 89(4):641–653 Differential control of Bmal1 circadian transcription by Kondratov RV, Kondratova AA, Gorbacheva VY, Vykhovanets OV, Antoch MP (2006) Early aging and age-related 123 Biogerontology (2018) 19:497–517 515

pathologies in mice deficient in BMAL1, the core com- stem cells to the biomechanical environment of the ponentof the circadian clock. Genes Dev endothelium on a flexible tubular silicone substrate. Bio- 20(14):1868–1873 materials 29(11):1610–1619 Kondratov RV, Vykhovanets O, Kondratova AA, Antoch MP Okazaki F, Matsunaga N, Okazaki H, Azuma H, Hamamura K, (2009) Antioxidant N-acetyl-L-cysteine ameliorates Tsuruta A, Ogino T, Hara Y, Suzuki T, Hyodo K (2016) symptoms of premature aging associated with the defi- Circadian clock in a mouse colon tumor regulates intra- ciency of the circadian protein BMAL1. Ageing cellular iron levels to promote tumor progression. J Biol 1(12):979–987 Chem 291(13):7017–7028 Kume K, Zylka MJ, Sriram S, Shearman LP, Weaver DR, Jin X, Paul MK, Bisht B, Darmawan DO, Chiou R, Ha VL, Wallace Maywood ES, Hastings MH, Reppert SM (1999) mCRY1 WD, Chon AC, Hegab AE, Grogan T, Elashoff DA, Alva- and mCRY2 are essential components of the negative limb Ornelas JA, Gomperts BN (2014) Dynamic changes in of the circadian clock feedback loop. Cell 98(2):193–205 intracellular ROS levels regulate airway basal stem cell Lu W, Meng QJ, Tyler NJ, Stokkan KA, Loudon AS (2010) A homeostasis through Nrf2-dependent Notch signalling. circadian clock is not required in an arctic mammal. Curr Cell Stem Cell 15(2):199–214 Biol 20(6):533–537 Paulose JK, Rucker EB III, Cassone VM (2012) Toward the Lu C, Yang Y, Zhao R, Hua B, Xu C, Yan Z, Sun N, Qian R beginning of time: circadian rhythms in metabolism pre- (2016) Role of circadian gene Clock during differentiation cede rhythms in clock gene expression in mouse embryonic of mouse pluripotent stem cells. Protein Cell stem cells. PLoS ONE 7(11):e49555 7(11):820–832 Pekovic-Vaughan V, Gibbs J, Yoshitane H, Yang N, Pathiran- Lutolf MP, Gilbert PM, Blau HM (2009) Designing materials to age D, Guo B, Sagami A, Taguchi K, Bechtold D, Loudon direct stem-cell fate. Nature 462(7272):433 A, Yamamoto M, Chan J, van der Horst GT, Fukada Y, Malik A, Kondratov RV, Jamasbi RJ, Geusz ME (2015) Cir- Meng QJ (2014) The circadian clock regulates rhythmic cadian clock genes are essential for normal adult neuro- activation of the NRF2/glutathione-mediated antioxidant genesis, differentiation, and fate determination. PLoS ONE defense pathway to modulate pulmonary fibrosis. Genes 10(10):e0139655 Dev 28(6):548–560 Mantovani C, Raimondo S, Haneef MS, Geuna S, Terenghi G, Pittendrigh CS (1960) Circadian rhythms and the circadian Shawcross SG, Wiberg M (2012) Morphological, molec- organization of living systems. In: Cold Spring Harbor ular and functional differences of adult bone marrow-and symposia on quantitative biology. vol 25. Cold Spring adipose-derived stem cells isolated from rats of different Harbor Laboratory Press, New York, pp 159–184 ages. Exp Cell Res 318(16):2034–2048 Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Matsu-ura T, Dovzhenok A, Aihara E, Rood J, Le H, Ren Y, Mosca JD, Moorman MA, Simonetti DW, Craig S, Mar- Rosselot AE, Zhang T, Lee C, Obrietan K, Montrose MH shak DR (1999) Multilineage potential of adult human (2016) Intercellular coupling of the cell cycle and circadian mesenchymal stem cells. Science 284(5411):143–147 clock in adult stem cell culture. Mol Cell 64(5):900–912 Plikus MV, Vollmers C, de la Cruz D, Chaix A, Ramos R, Panda Mauney JR, Kaplan DL, Volloch V (2004) Matrix-mediated S, Chuong CM (2013) Local circadian clock gates cell retention of osteogenic differentiation potential by human cycle progression of transient amplifying cells during adult bone marrow stromal cells during ex vivo expansion. regenerative hair cycling. Proc Natl Acad Sci Biomaterials 25(16):3233–3243 110(23):E2106–E2115 Me´ndez-Ferrer S, Lucas D, Battista M, Frenette PS (2008) Plikus MV, Van Spyk EN, Pham K, Geyfman M, Kumar V, Hematopoietic stem cell release is regulated by circadian Takahashi JS, Andersen B (2015) The circadian clock in oscillations. Nature 452(7186):442–447 skin: implications for adult stem cells, tissue regeneration, Mengatto CM, Mussano F, Honda Y, Colwell CS, Nishimura I cancer, aging, and immunity. J Biol Rhythm (2011) Circadian rhythm and cartilage extracellular matrix 30(3):163–182 genes in osseointegration: a genome-wide screening of Puram RV, Kowalczyk MS, de Boer CG, Schneider RK, Miller implant failure by vitamin D deficiency. PLoS ONE PG, McConkey M, Tothova Z, Tejero H, Heckl D, Ja¨ra˚sM, 6(1):e15848 Chen MC (2016) Core circadian clock genes regulate Moerman EJ, Teng K, Lipschitz DA, Lecka-Czernik B (2004) leukemia stem cells in AML. Cell 165(2):303–316 Aging activates adipogenic and suppresses osteogenic Reppert SM, Weaver DR (2002) Coordination of circadian programs in mesenchymal marrow stroma/stem cells: the timing in mammals. Nature 418(6901):935–941 role of PPAR-c2 transcription factor and TGF-b/BMP Rogers EH, Fawcett S, Pekovic-Vaughan V, Hunt JA (2017) signaling pathways. Aging Cell 3(6):379–389 Comparing circadian dynamics in primary derived stem Morrison SJ, Kimble J (2006) Asymmetric and symmetric stem- cells from different sources of human adult tissue. Stem cell divisions in development and cancer. Nature Cell Int. https://doi.org/10.1155/2017/2057168 441(7097):1068–1074 Rogers EH, Pekovic-Vaughan V, Hunt JA (2018) Mechanical Nam D, Chatterjee S, Yin H, Liu R, Lee J, Yechoor VK, Ma K stretch and chronotherapeutic techniques for progenitor (2015) Novel function of Rev-erba in promoting brown cell transplantation and biomaterials. BioMedicine adipogenesis. Sci Rep 5:11239 8(3):3–12 O’Neill JS, Reddy AB (2011) Circadian clocks in human red Ross SE, Hemati N, Longo KA, Bennett CN, Lucas PC, blood cells. Nature 469(7331):498 Erickson RL, MacDougald OA (2000) Inhibition of adi- O’Cearbhaill ED, Punchard MA, Murphy M, Barry FP, pogenesis by Wnt signaling. Science 289(5481):950–953 McHugh PE, Barron V (2008) Response of mesenchymal 123 516 Biogerontology (2018) 19:497–517

Samsa WE, Vasanji A, Midura RJ, Kondratov RV (2016) Tsinkalovsky O, Rosenlund B, Laerum OD, Eiken HG (2005) Deficiency of circadian clock protein BMAL1 in mice Clock gene expression in purified mouse hematopoietic results in a low bone mass phenotype. Bone 84:194–203 stem cells. Exp Hematol 33(1):100–107 Sen B, Xie Z, Case N, Ma M, Rubin C, Rubin J (2008) Umemura Y, Koike N, Matsumoto T, Yoo SH, Chen Z, Yasu- Mechanical strain inhibits adipogenesis in mesenchymal hara N, Takahashi JS, Yagita K (2014) Transcriptional stem cells by stimulating a durable b-catenin signal. program of Kpna2/Importin-a2 regulates cellular differ- Endocrinology 149(12):6065–6075 entiation-coupled circadian clock development in mam- Shearman LP, Sriram S, Weaver DR, Maywood ES, Chaves I, malian cells. Proc Natl Acad Sci 111(47):E5039–E5048 Zheng B, Kume K, Chi Li C, Hastings MH, Reppert SM Umemura Y, Koike N, Ohashi M, Tsuchiya Y, Meng QJ, (2000) Interacting molecular loops in the mammalian cir- Minami Y, Hara M, Hisatomi M, Yagita K (2017) cadian clock. Science 288(5468):1013–1019 Involvement of posttranscriptional regulation of Clock in Shimba S, Ishii N, Ohta Y, Ohno T, Watabe Y, Hayashi M, the emergence of circadian clock oscillation during mouse Wada T, Aoyagi T, Tezuka M (2005) Brain and muscle development. Proc Natl Acad Sci 114(36):E7479–E7488 Arnt-like protein-1 (BMAL1), a component of the molec- Van Laake LW, Lu¨scher TF, Young ME (2018) The circadian ular clock, regulates adipogenesis. Proc Natl Acad Sci clock in cardiovascular regulation and disease: lessons USA 102(34):12071–12076 from the nobel prize in physiology or medicine 2017. Eur Silver R, LeSauter J, Tresco PA, Lehman MN (1996) A dif- Heart J 39(24):2326–2329 fusible coupling signal from the transplanted suprachias- Wang J, Morita Y, Han B, Niemann S, Loffler B, Rudolph KL matic nucleus controlling circadian locomotor rhythms. (2016) Per2 induction limits lymphoid-biased hematopoi- Nature 382(6594):810–813 etic stem cells and lymphopoiesis in the context of DNA Simoni A, Wolfgang W, Topping MP, Kavlie RG, Stanewsky R, damage and ageing. Nat Cell Biol 18(5):480–501 Albert JT (2014) A mechanosensory pathway to the Dro- Weger M, Diotel N, Dorsemans AC, Dickmeis T, Weger BD sophila circadian clock. Science 343(6170):525–528 (2017) Stem cells and the circadian clock. Dev Biol Singh A, Elisseeff J (2010) Biomaterials for stem cell differ- 431:111–123 entiation. J Mater Chem 20(40):8832–8847 Williams CT, Barnes BM, Buck CL (2011) Daily body tem- Solanas G, Peixoto FO, Perdiguero E, Jardı´ M, Ruiz-Bonilla V, perature rhythms persist under the midnight sun but are Datta D, Symeonidi A, Castellanos A, Welz PS, Caballero absent during hibernation in free-living arctic ground JM, Benitah SA (2017) Aged stem cells reprogram their squirrels. Biol Lett 8:31–34 daily rhythmic functions to adapt to stress. Cell Williams CT, Barnes BM, Richter M, Buck CL (2012) Hiber- 170(4):678–692 nation and circadian rhythms of body temperature in free- Stenderup K, Justesen J, Eriksen EF, Rattan SI, Kassem M living Arctic ground squirrels. Physiol Biochem Zool (2001) Number and proliferative capacity of osteogenic 85(4):397–404 stem cells are maintained during aging and in patients with Williams CT, Radonich M, Barnes BM, Buck CL (2017) Sea- osteoporosis. J Bone Miner Res 16(6):1120–1129 sonal loss and resumption of circadian rhythms in hiber- Stringari C, Wang H, Geyfman M, Crosignani V, Kumar V, nating arctic ground squirrels. J Comp Physiol B Takahashi JS, Andersen B, Gratton E (2015) In vivo single- 187(5–6):693–703 cell detection of metabolic oscillations in stem cells. Cell Wu X, Zvonic S, Floyd ZE, Kilroy G, Goh BC, Hernandez TL, Rep 10(1):1–7 Eckel RH, Mynatt RL, Gimble JM (2007) Induction of Sun YY, Bai WW, Wang B, Lu XT, Xing YF, Cheng W, Liu circadian gene expression in human subcutaneous adipose- XQ, Zhao YX (2014) Period 2 is essential to maintain early derived stem cells. Obesity 15(11):2560–2570 endothelial progenitor cell function in vitro and angio- Wu X, Yu G, Parks H, Hebert T, Goh BC, Dietrich MA, Pelled genesis after myocardial infarction in mice. J Cell Mol Med G, Izadpanah R, Gazit D, Bunnell BA, Gimble JM (2008) 18(5):907–918 Circadian mechanisms in murine and human bone marrow Sun L, Qu L, Zhu R, Li H, Xue Y, Liu X, Fan J, Fan H (2016) mesenchymal stem cells following dexamethasone expo- Effects of mechanical stretch on cell proliferation and sure. Bone 42(5):861–870 matrix formation of mesenchymal stem cell and anterior Yagita K, Horie K, Koinuma S, Nakamura W, Yamanaka I, cruciate ligament fibroblast. Stem Cells Int. https://doi.org/ Urasaki A, Shigeyoshi Y, Kawakami K, Shimada S, 10.1155/2016/9842075 Takeda J, Uchiyama Y (2010) Development of the circa- Thomson JA, Itskovitz-Eldor J, Shapiro SS, Waknitz MA, dian oscillator during differentiation of mouse embryonic Swiergiel JJ, Marshall VS, Jones JM (1998) Embryonic stem cells in vitro. Proc Natl Acad Sci 107(8):3846–3851 stem cell lines derived from human blastocysts. Science Yamazaki S, Numano R, Abe M, Hida A, Takahashi RI, Ueda 282(5391):1145–1147 M, Block GD, Sakaki Y, Menaker M, Tei H (2000) Tokalov SV, Gru¨ner S, Schindler S, Wolf G, Baumann M, Resetting central and peripheral circadian oscillators in Abolmaali N (2007) Age-related changes in the frequency transgenic rats. Science 288(5466):682–685 of mesenchymal stem cells in the bone marrow of rats. Yang N, Williams J, Pekovic-Vaughan V, Wang P, Olabi S, Stem Cells and Development 16(3):439–446 McConnell J, Gossan N, Hughes A, Cheung J, Streuli CH, Tontonoz P, Hu E, Spiegelman BM (1994) Stimulation of adi- Meng QJ (2017) Cellular mechano-environment regulates pogenesis in fibroblasts by PPARc2, a lipid-activated the mammary circadian clock. Nat Commun 8:14287 transcription factor. Cell 79(7):1147–1156 Zagni C, Almeida LO, Balan T, Martins MT, Rosselli-Murai LK, Papagerakis P, Castilho RM, Squarize CH (2017) PTEN mediates activation of core clock protein BMAL1 123 Biogerontology (2018) 19:497–517 517

and accumulation of epidermal stem cells. Stem Cell Rep and chemoresistance of colorectal cancer stem-like cells 9:304–314 via inhibition of notch and b-catenin signaling. Oncol Res Zhang F, Sun H, Zhang S, Yang X, Zhang G, Su T (2017) Featur Preclin Clin Cancer Ther 25(5):709–719 Overexpression of PER3 inhibits self-renewal capability

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